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WO2018193090A2 - Process for preparation of eliglustat hemitartrate and intermediates thereof - Google Patents

Process for preparation of eliglustat hemitartrate and intermediates thereof Download PDF

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Publication number
WO2018193090A2
WO2018193090A2 PCT/EP2018/060185 EP2018060185W WO2018193090A2 WO 2018193090 A2 WO2018193090 A2 WO 2018193090A2 EP 2018060185 W EP2018060185 W EP 2018060185W WO 2018193090 A2 WO2018193090 A2 WO 2018193090A2
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Prior art keywords
eliglustat
formula
hemitartrate
suitable solvent
reacting
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PCT/EP2018/060185
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French (fr)
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WO2018193090A3 (en
Inventor
Kanaram Hanumanprasad KUMAWAT
Brijesh Rajendrakumar PATEL
Nilesh Mansukhlal Thumar
Joseph Prabahar UPADHYAY
Joseph Prabahar Koilpillai
Virendrakumar Agarwal
Parva Yogeshchandra Purohit
Arif Badrulhusan Siddiqui
Krushnakant Natvarbhai PATEL
Vipul Veljibhai GONDALIYA
Ankit Ramjibhai BUHA
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Amneal Pharmaceuticals Company Gmbh
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Publication of WO2018193090A2 publication Critical patent/WO2018193090A2/en
Publication of WO2018193090A3 publication Critical patent/WO2018193090A3/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D319/00Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/101,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/141,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/161,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18Ethylenedioxybenzenes, not substituted on the hetero ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present disclosure relates to a novel process for the preparation of eliglustat hemitartrate and intermediates thereof.
  • the present disclosure also relates to stable amorphous form of eliglustat hemitartrate, process for its preparation and pharmaceutical composition thereof.
  • Eliglustat tartrate is chemically described as N-((lR,2R)-l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-l-hydroxy-3-(pyrrolidin-l-yl)propan-2-yl) octanamide (2R,3R)-2,3-dihydroxysuccinate and is marketed as Cerdelga® by Genzyme Corp. for the long term treatment of adult patients with Gaucher disease type 1.
  • Eliglustat hemitartrate has the structure of formula (I).
  • U.S. Patent No. 7,196,205 discloses a process for the preparation of eliglustat as shown in scheme-I.
  • phenyl-a- bromoacetate is reacted with S-(+)-phenyl glycinol to provide (5S)-5-phenylmorpholin-2-one, which is condensed with benzodioxolane-6-carboxaldehyde to provide (lR,3S,5S,8aS)-l,3-bis- (2',3'-dihydro-benzo[l,4]dioxin-6'-yl)-5-phenyl-tetrahydro-oxazolo[4,3-c][l,4]oxazin-8-one.
  • the resulting cycloadduct compound is reacted with pyrrolidine followed by methanol and aqueous hydrochloric acid solution to provide (2S,3R,l"S)-3-(2',3'-dihydro-benzo[l,4]dioxin-6'-yl)-3- hydroxy-2-(2"-hydroxy-l"-phenyl-ethylamino)-l-pyrrolidin-l-yl-propan-l-one, which is further reduced with lithium aluminum hydride and debenzylated with 20% palladium hydroxide on carbon to yield (lR,2R)-2-amino-l-(2',3'-dihydro-benzo[l,4]dioxin-6'-yl)-3-pyrrolidin-l-yl- propan-l-ol.
  • the final step involves condensation of the resulting product with octanoic acid N- hydroxysuccinimide ester to yield eliglust
  • CN105646442A discloses reaction of (lR,2R)-2-amino- dihydrobenzo[b][l,4]dioxin-6-yl)-3-(pyrrolidin-l-yl)propan-l-ol with boc anhydride followed by benzyl bromide and then de-protection of the boc group to provide (lR,2R)-l-(benzyloxy)-l- (2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-3-(pyrrolidin-l-yl)propan-2-amine. Condensation of the resulting compound with octanoyl chloride yields benzylated eliglustat which is debenzylated by hydrogenation to provide eliglustat.
  • U.S. Patent No. 6,916,802 discloses a process for preparing ceramide-like compounds which involves resolution of isomers by chromatography. However, this process is not suitable for large scale industrial preparations. Therefore, there is a need to develop a simple iterative process for the preparation of eliglustat and its tartrate salt which is economical and applicable on an industrial scale.
  • U.S. Patent Application Publication No. 2013/137743 discloses crystalline form A of eliglustat hemitartrate and a process for preparation thereof.
  • Amorphous eliglustat hemitartrate is known from WO2016/001885 and IN201621009771, in which the amorphous eliglustat hemitartrate is obtained by spray drying or by dissolving eliglustat hemitartrate in a solvent or a mixture of solvent, followed by evaporation under reduced pressure to obtain solid residue.
  • the said process is not suitable for industrial application as the residue obtained has a higher amount of residual solvent.
  • the obtained amorphous material is not stable and is hygroscopic in nature, and therefore is not suitable in handling and use for pharmaceutical developments.
  • amorphous eliglustat hemitartrate obtained herein is non-hygroscopic, substantially free from residual solvent, industrially scalable for bulk manufacturing and stable towards polymorphic conversion at ambient conditions.
  • One or more embodiments provide a simple and commercially advantageous process for the preparation of amorphous eliglustat hemitartrate.
  • the present invention provides processes for the preparation of eliglustat or its tartrate salt (I). Also provided are: a stable amorphous form of eliglustat hemitartrate, a process for preparation thereof, a pharmaceutical composition comprising the same, and use of eliglustat hemitartrate for treatment of gaucher disease.
  • a process for preparation of eliglustat or its tartrate salt comprises:
  • a process for preparation of eliglustat or its tartrate salt comprises: (a) reacting racemic eliglustat of formula II)
  • di-p-toluoyl-D-tartaric acid in the presence of a suitable solvent to provide di-p- toluoyl-D-tartrate salt of formula (VIII); optionally purifying the di-p-toluoyl-D-tartrate salt of formula (VIII);
  • a process for preparation of racemic eliglustat of formula (VII) comprises:
  • a process for recycling racemic eliglustat of formula (VII) or its salt comprises:
  • eliglustat or its salt is prepared substantially free of impurity eliglustat N-oxide of formula (X)
  • novel intermediates N-(2-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-2-oxoethyl)octan-amide of formula (V); N-(l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l-yl)propan-2-yl)octanamide of formula (VI); oxalate salt of N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l- yl)propan-2-yl)octanamide of formula (VI); and di-p-toluoyl-D-tartrate salt of eliglustat of formula (VIII), and their pharmaceutically acceptable solvates and hydrates thereof; processes for their preparation; and
  • a process for preparation of stable amorphous eliglustat hemitartrate comprises:
  • the stable amorphous form of eliglustat hemitartrate is characterized by X-ray powder diffraction as depicted in Fig. 1 and/or Fig. 2.
  • a pharmaceutical composition comprises the stable amorphous form of eliglustat hemitartrate together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • stable amorphous eliglustat hemitartrate is used for treatment of Gaucher disease.
  • Fig. 1 The X-ray diffraction pattern of stable amorphous eliglustat hemitartrate obtained after drying at about 50-55° C for about 4-6 hours under reduced pressure.
  • Fig. 2 The X-ray diffraction pattern of stable amorphous eliglustat hemitartrate after 1 month storage at ambient temperature.
  • Lewis acid is used herein to refer to a substance which can accept an unshared electron pair from another molecule.
  • ambient temperature refers to a temperature in the range of about 20° C to about 35° C.
  • Suitable solvent means a single or a combination of two or more solvents.
  • the term "obtaining" means isolating by way of filtration, filtration under vacuum, centrifugation, decantation and the like.
  • the product obtained may be further or additionally dried to achieve the desired moisture values.
  • the product may be dried in a tray drier, dried under vacuum and/or in a fluid bed drier.
  • heartrate salt covers monotartrate and hemitartrate.
  • a process for preparation of eliglustat or its tartrate salt comprises:
  • the resolution solvent may be a solvent or solvent mixture in which the racemic eliglustat and chiral acid are soluble, either completely or partially.
  • Solvents that may be used for salt formation include, but are not limited to, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol and the like; halogenated hydrocarbons such as dichloromethane, chlorobenzene, chloroform and the like or mixtures thereof.
  • Chiral acids can be used for resolution, which facilitates the synthesis of desired enantiomers with absolute configurational assignment.
  • Suitable chiral acids include any optically enriched chiral acid capable of forming an isolable salt with racemic eliglustat of formula (VIII).
  • Non-limiting examples of chiral acids include one or more of: mandelic acid, malic acid, camphor sulfonic acid, di-p-toluoyl-D-tartaric acid, di-m-toluoyl-D-tartaric acid, and di-benzoyl- D-tartaric acid.
  • di-0,0'-aroyl-D- or L-tartaric acid can be used as a chiral acid to resolve racemic eliglustat of formula (VII). More preferably, the chiral acid is di-p-toluoyl-D- tartaric acid.
  • Suitable bases include any base, either organic or inorganic, which allow release of the eliglustat free base from its salt form. Bases include, but are not limited to, alkali or alkaline earth metal carbonates such as: sodium carbonate, potassium carbonate; bicarbonate such as sodium bicarbonate, potassium bicarbonate; and hydroxide such as sodium hydroxide, potassium hydroxide; or mixtures thereof.
  • a process for preparation of eliglustat or its tartrate salt comprises the steps of:
  • di-p-toluoyl-D-tartaric acid in the presence of a suitable solvent to provide di-p- toluoyl-D-tartrate salt of formula (VIII); optionally purifying the di-p-toluoyl-D-tartrate salt of formula (VIII)
  • racemic eliglustat of formula (VII) is reacted with di-p-toluoyl-D-tartaric acid in the presence of a suitable solvent to provide di-p-toluoyl-D-tartrate salt of formula (VIII).
  • Solvents that may be used for salt formation include, but are not limited to: alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol and the like; and halogenated hydrocarbons such as dichloromethane, chlorobenzene, chloroform and the like; or mixtures thereof.
  • Eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) may be purified from solvents selected from, but not limited to, alcohols such as methanol, ethanol, isopropanol and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like; polar aprotic solvents such as dimethylformamide, acetamide and the like; ethers such as tetrahydrofuran, methyl tert. butyl ether and the like; and water; or mixtures thereof.
  • solvents selected from, but not limited to, alcohols such as methanol, ethanol, isopropanol and the like; ketones such as acetone, methyl ethyl ketone, methyl is
  • eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) is reacted with a suitable base in the presence of a solvent to provide eliglustat free base of formula (IX).
  • Solvents include, but are not limited to: halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chlorobenzene, chloroform and the like; hydrocarbons such as toluene, xylene and the like; and water; or mixtures thereof.
  • Bases include, but are not limited to: alkali or alkaline earth metal carbonate such as sodium carbonate, potassium carbonate; bicarbonate such as sodium bicarbonate, potassium bicarbonate; and hydroxide such as sodium hydroxide, potassium hydroxide; or mixtures thereof.
  • the reaction may be carried out with dichloromethane, water and potassium carbonate to provide eliglustat free base of formula (IX).
  • Eliglustat free base of formula (IX) may be purified from solvents selected from, but not limited to: hydrocarbons such as toluene, xylene, hexane, heptane, cyclohexane and the like; polar aprotic solvents such as dimethylformamide, acetamide and the like; ethers such as tetrahydrofuran, methyl tert. butyl ether and the like; and water; or mixtures thereof.
  • solvents selected from, but not limited to: hydrocarbons such as toluene, xylene, hexane, heptane, cyclohexane and the like; polar aprotic solvents such as dimethylformamide, acetamide and the like; ethers such as tetrahydrofuran, methyl tert. butyl ether and the like; and water; or mixtures thereof.
  • eliglustat free base of formula (IX) is reacted with L-(+)-tartaric acid in the presence of a suitable solvent to provide eliglustat tartrate, preferably eliglustat hemitartrate (I).
  • Solvents include, but are not limited to: hydrocarbons such as toluene, xylene and the like; alcohols such methanol, ethanol, isopropanol and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; and water; or mixtures thereof.
  • the reaction may be carried out with toluene, water and L-(+)-tartaric acid to provide eliglustat hemitartrate (I).
  • the reaction may be carried out at a temperature of about 10° C to about 130° C, preferably at about 20° C to about 80° C.
  • the reaction of eliglustat free base of formula (IX) with L-(+)-tartaric acid may be carried out for about 15 min. to about 4 hours, preferably for about 30 min. to about 2 hours.
  • Eliglustat hemitartrate of formula (I) may be isolated from the reaction mixture by evaporation, filtration, concentration, precipitation, cooling, centrifugation, decantation or any other suitable technique known in the art.
  • Eliglustat hemitartrate of formula (I) may be isolated from the reaction mixture using solvent.
  • Solvent used for isolation may include, but are not limited to: hydrocarbons such as toluene, xylene, hexane, heptane, cyclohexane and the like; and water; or mixtures thereof.
  • a process for preparation of racemic eliglustat of formula (VII) comprises:
  • the obtained compound of formula (III) is in situ reacted with an aminating agent and hydrochloric acid to provide 2-amino-l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)ethan-l-one hydrochloride of formula (IV).
  • Aminating agents that may be used include, but are not limited to: hexamine, ammonia and the like.
  • Solvents that may be used include, but are not limited to: halogenated hydrocarbons such as dichloromethane, chlorobenzene, chloroform and the like; hydrocarbon such as toluene, xylene and the like; or mixtures thereof.
  • Non-limiting examples of the octanoic acid derivatives include: corresponding octanoyl halide, symmetric or mixed carboxylic anhydride, and the corresponding sulfonyloxy or imidazole derivatives.
  • the reaction can be carried out using condensing agents such as CDI (carbonyldiimidizole), HOBt (1-hydroxybenzotriazole), HATU ((0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate)), TATU ((0- (7-azabenzotriazole-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate)), EDC (l-ethyl-3-(3- dimethylaminopropyl)carbodiimide), and DCC ( ⁇ , ⁇ '-dicyclohexylcarbodiimide) in
  • Solvents that may be used include, but are not limited to: halogenated hydrocarbons such as dichloromethane, chlorobenzene, chloroform and the like; hydrocarbon such as toluene, xylene and the like; and ethers such as tetrahydrofuran (THF) and diethyl ether; or mixtures thereof.
  • halogenated hydrocarbons such as dichloromethane, chlorobenzene, chloroform and the like
  • hydrocarbon such as toluene, xylene and the like
  • ethers such as tetrahydrofuran (THF) and diethyl ether; or mixtures thereof.
  • Bases that may be used include, but are not limited to: diisopropylethylamine (DIPEA), triethylamine (TEA), diethylamine (DEA), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), imidazole, ⁇ , ⁇ -dimethyl aniline, 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), potassium carbonate, sodium carbonate, and the like.
  • DIPEA diisopropylethylamine
  • TEA triethylamine
  • DEA diethylamine
  • DBU 1,8- diazabicyclo[5.4.0]undec-7-ene
  • imidazole ⁇ , ⁇ -dimethyl aniline, 1,5- diazabicyclo[4.3.0]non-5-ene (DBN)
  • DBN diazabicyclo[4.3.0]non-5-ene
  • the acetylation of formula (IV) may be performed
  • compound of formula (VI) is treated with oxalic acid in the presence of a suitable solvent to provide oxalate salt of formula (VI).
  • Solvents that may be used for salt formation include, but are not limited to: alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, or mixtures thereof.
  • Solvents that may be used for reduction include, but are not limited to: alcohols such as methanol, ethanol, n- propanol, isopropanol, n-butanol, and t-butanol, or mixtures thereof.
  • Reduction can be performed by catalytic hydrogenation or with a hydrogenation reducing agent.
  • a catalytic hydrogenation reducing agent may include: noble metal catalyst such as Pd, Pt, Rh and Ru supported on carbon, or using a complex of such metal such as palladium, palladium-carbon, palladium hydroxide-carbon, platinum oxide, copper chromite, palladium acetate, platinum- carbon, palladium-alumina, and Raney nickel.
  • a hydrogenation reducing agent may include: sulfite compounds such as sodium bisulfite, sodium sulfite, sodium pyrosulfite, ammonium sulfite, ammonium sulfite monohydrate, or ammonium bisulfite; tetra lower alkyl ammonium borohydrides such as tetra methyl ammonium borohydride, tetra ethyl ammonium borohydride, tetra-n-butyl ammonium borohydride, tetra-n-butyl ammonium cyanoborohydride, sodium cyanoborohydride, lithium cyanoborohydride, sodium borohydride, potassium borohydride, lithium aluminum hydride and diborane.
  • sulfite compounds such as sodium bisulfite, sodium sulfite, sodium pyrosulfite, ammonium sulfite, ammonium sulfite monohydrate, or ammonium bisulfite
  • eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) is directly converted to eliglustat hemitartrate of formula (I) without isolating the eliglustat free base of formula (IX).
  • eliglustat free base of formula (IX) is not isolated but rather converted in situ to the eliglustat hemitartrate of formula (I).
  • Eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) is reacted with a suitable base in the presence of a solvent to provide eliglustat free base of formula (IX), which was in situ reacted with L-(+)-tartaric acid in the presence of a suitable solvent to provide eliglustat tartrate, preferably eliglustat hemitartrate of formula (I).
  • the undesired isomer of eliglustat can be recovered from the mother liquors of the resolution step by oxidation, followed by epimerization and reduction to provide racemic eliglustat, which can be recycled for further resolution.
  • a process for recycling racemic eliglustat of formula (VII) or its salt comprises:
  • the mother liquor obtained after the isolation of the desired eliglustat di-p-toluoyl-D- tartrate salt of formula (VIII) may be oxidized by oxidizing agent such as potassium dichromate, potassium permanganate, hydrogen peroxide, sodium hypochlorite, sodium hypobromite, chromium trioxide in dilute sulfuric acid, mixture of potassium dichromate and dilute sulfuric acid, Jones oxidation, Swern oxidation, Baeyer-Villiger oxidation, Oppenauer oxidation, and Pinnick oxidation, or mixtures thereof.
  • Oxidation may be carried out in the presence of a solvent such as: ketone, ether, and a halogenated hydrocarbon, or mixtures thereof.
  • the obtained compound of formula (VI) may be epimerized in the presence or absence of base. Reduction of N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l-yl)propan-2-yl)octanamide of formula (VI) or its oxalate salt may carried out as described above.
  • eliglustat or its salt is prepared having a relatively low content of one or more organic impurities compared to known organic impurities in the art.
  • a content of eliglustat N-oxide impurity of formula (X) can be controlled to a minimum level by in situ reacting the eliglustat base of formula (IX) with tartaric acid and thereby obtaining eliglustat hemitartrate salt substantially free from eli lustat N-oxide impurity of formula (X)
  • novel intermediates N-(2-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-2-oxoethyl) octanamide of formula (V); N-(l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l-yl)propan-2-yl)octanamide of formula (VI); oxalate salt of N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l- yl)propan-2-yl) octanamide of formula (VI); and di-p-toluoyl-D-tartrate salt of eliglustat of formula (VIII), and their pharmaceutically acceptable solvates and hydrates thereof; processes for their preparation;
  • amorphous eliglustat hemitartrate is non-hygroscopic and does not convert into crystalline form at ambient temperature. Also, amorphous eliglustat hemitartrate, as described herein, is stable against thermal degradation during drying at elevated temperature.
  • the amorphous eliglustat hemitartrate is non-hygroscopic.
  • the change in the total weight of amorphous eliglustat hemitartrate was found to be about 0.02 weight percent.
  • the amorphous eliglustat hemitartrate may be characterized by such non- hygroscopicity upon exposure to an atmosphere of about 36% humidity for a period of 20 hours. This non-hygroscopic nature of the amorphous eliglustat hemitartrate renders it exceptionally suitable for use in preparing pharmaceutical compositions.
  • the stable amorphous eliglustat hemitartrate refers to an amorphous form of eliglustat hemitartrate that remains stable towards conversion to crystalline form at ambient temperature for a period of at least 1 month, showing no change in polymorphic form by X-ray powder diffraction when placed at a temperature of 25 ⁇ 2° C at a relative humidity of 60 +5% for 1 month, or at a temperature of 5 ⁇ 2° C for 1 month.
  • the stable amorphous eliglustat hemitartrate is substantially free of residual solvent, wherein the term “substantially free of residual solvent” refers to the stable amorphous form of eliglustat hemitartrate having less than 5000 ppm of residual solvent.
  • a process for preparation of stable amorphous eliglustat hemitartrate comprises:
  • the starting material to be used for the preparation of stable amorphous eliglustat hemitartrate can be obtained by a method known to a person of ordinary skill in the art including, for example, the method described in WO 2016/001885 and/or US Publication No. 2013/0137743, which are incorporated herein by reference.
  • the suspension of eliglustat hemitartarate can be obtained by known methods that include direct use of a reaction mixture containing eliglustat hemitartarate that is obtained in the course of its synthesis, or suspension of eliglustat hemitartarate in suitable solvent or mixture of solvents.
  • the suspension of eliglustat hemitartrate may be a clear solution with homogenous mixture or a suspension or slurry with a heterogeneous mixture in suitable solvent.
  • suitable solvent may include, but is not limited to,: hydrocarbons such as toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene and the like; alcohols such as methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol and the like; ketones such as acetone, butanone, 2-pentanone, 3- pentanone, methyl butyl ketone, methyl isobutyl ketone and the like; esters such as methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobuty
  • solvent is removed to obtain a residue.
  • the suspension of eliglustat hemitartrate in solvent may be distilled until partial removal of solvent by distillation under vacuum.
  • Suitable techniques that can be used for the removal of solvent include but not limited to: evaporation, simple evaporation, decantation, and rotational drying, or any other suitable technique known in the art.
  • the solvent may be removed, optionally under reduced pressures, at temperature less than about 150° C, less than about 100° C, less than about 75° C, less than about 50° C, or any other suitable temperature.
  • eliglustat hemitartrate is suspended in toluene under reflux conditions and the water contained in it is removed by azeotropic distillation.
  • the solvents of (b) include but are not limited to a group of solvents in which eliglustat hemitartrate is insoluble or poorly soluble or partially soluble.
  • the solvents may include, but are not limited to: ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol and the like; and hydrocarbons such as toluene, xylene, hexane, cyclohexane, heptane and the like; or mixtures thereof.
  • Embodiments of the process may further comprise dissolving the obtained eliglustat hemitartrate in solvent and removing the solvent to obtain a residue.
  • the residue is treated with suitable solvent to obtain an amorphous form of eliglustat hemitartrate.
  • an amorphous form of eliglustat hemitartrate is obtained.
  • the isolation may be effected by removing the solvent. Suitable techniques which can be used for the removal of solvent include but are not limited to filtration, decantation or any other suitable technique known in the art.
  • suitable techniques which can be used for obtaining an amorphous form of eliglustat hemitartrate include, but not limited to, filtration under vacuum, evaporation, decantation or any other suitable technique known in the art.
  • the obtained amorphous eliglustat hemitartrate from (c) may be collected by using techniques such as by scraping or by shaking the container or other techniques specific to the equipment used.
  • the isolated solid may be optionally further dried to afford an amorphous form of eliglustat hemitartrate. Drying can be carried out under reduced pressure, vacuum tray drying or air drying. Drying can be carried out for any desired times until the required product quality is achieved.
  • the obtained eliglustat hemitartrate may be dried under vacuum at about 50° C to 70° C for 6-12 hours to obtain the amorphous form substantially free from residual solvent.
  • the obtained amorphous eliglustat hemitartrate is stable under ordinary stability conditions at least for 1 month and does not change to crystalline form.
  • the stable amorphous form of eliglustat hemitartrate is characterized by the X-ray powder diffraction substantially as depicted in Fig. 1 and/or Fig. 2.
  • a pharmaceutical composition comprises the stable amorphous form of eliglustat hemitartrate together with one or more pharmaceutically acceptable carriers or excipients.
  • compositions containing stable amorphous eliglustat hemitartrate may be prepared by using excipients such as diluents, binders, wetting agents, disintegrating agents, surface active agents and lubricants.
  • excipients such as diluents, binders, wetting agents, disintegrating agents, surface active agents and lubricants.
  • Various modes of administration of the pharmaceutical compositions of the invention may be selected depending on the therapeutic purpose for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories or injection preparations.
  • stable amorphous eliglustat hemitartrate is for treatment of Gaucher disease.
  • the pharmaceutical compositions containing stable amorphous eliglustat hemitartrate disclosed herein can be used for treatment of Gaucher disease.
  • HPLC purity of eliglustat hemitartrate was determined using a symmetry CI 8 (250* 4.6mm, 5 ⁇ ) column with a flow rate of 1.2 ml/min; column oven temperature: 40° C; sample tray temperature: ambient; detector: UV at 275nm; injection volume: 20 ⁇ 1; runtime: 65 min.
  • the synthetic reaction scheme for eliglustat hemitartrate is as shown in Scheme-Ill.
  • Eliglustate hemitartrate Eliglustat
  • the reaction mixture was allowed to warm at 25-35° C and then water (700 ml) and dichloromethane (700 ml) were added to the reaction mixture.
  • the pH of the reaction mixture was adjusted to 8.0-10.0 with 20% potassium carbonate solution.
  • the reaction mixture was stirred for 30 min. and then the layers were separated.
  • the organic layer was washed with water (200 ml), distilled out under vacuum and then azeotroped with methanol (100 ml).
  • the obtained crude product (VII) was dissolved in methanol (700 ml), and then a solution of di-p-tolyl-D-tartaric acid (74.5 g) in methanol (300 ml) was added at 50-60° C.
  • the reaction mixture was stirred at 50-60° C for 1 h. Then the reaction mixture was cooled at 25-35° C and stirred for 2 h. The solid was filtered and washed with methanol (50 ml X 2). Suck dry and mixed the obtained wet cake with methanol (750 ml). The reaction mixture was heated to reflux for 1 h, then the reaction mixture was cooled at 25-35° C and stirred for 2 h. The solid was filtered and washed with methanol (50 ml X 2). The solid was dried at 25-35° C for 2 h and then at 55-65° C for 8 h to give the title product (43.32 g).
  • Cyclohexane (40 ml) was added to the obtained residue and stirred for 30 min. The cyclohexane was distilled out under vacuum and then the residue degassed under vacuum to remove traces of solvent. Cyclohexane (200 ml) was added to the obtained residue and stirred for 1 h at 45-55° C. The reaction mixture was cooled to 25-35° C and stirred for 1 h. The solid was filtered and washed with cyclohexane (20ml X 2). The solid was dried at 25-35° C for 2 h and then at 45-55° C for 4 h to give the title product (19.5 g).
  • the organic layer was filtered through a Hyflo bed and washed with toluene.
  • a solution of L-(+) tartaric acid (9.4 g) in water (200 ml) was added to the obtained toluene layer at 25-35°C and stirred for 30 min.
  • the layers were separated, and the aqueous layer (containing product)was filtered to remove particulate matter and washed with water (50 ml).
  • the aqueous layer was distilled out under vacuum below 60° C to provide residue. Water (75 ml) was added to the residue at 35-45°C and stirred to provide a clear solution.
  • the obtained solution was dried in a vacuum tray dryer at 35-45°C for 2 h and then at 45-55° C for 12 h.
  • the obtained product was further dried in a vacuum tray dryer at 45-55°C until the water content was not more than 1.0 %w/w to give the title product (49.89 g).
  • the layers were separated and the organic layer was washed with dilute aqueous ammonia solution (-2% w/v) (50 ml) followed by water (50 ml X 3).
  • the organic layer was filtered through a Hyflo bed and washed with toluene (25 ml).
  • a solution of L-(+) tartaric acid (2.37 g) in water (50 ml) was added to the obtained toluene layer at 25-35° C and stirred for 30 min.
  • the layers were separated, and the aqueous layer (containing product)was filtered to remove particulate matter and washed with water (7 ml).
  • the aqueous layer was distilled out under vacuum below 60° C to provide residue.
  • Residual solvent content (toluene): 0.01wt%.
  • the obtained amorphous eliglustat hemitartrate was kept in an open air having about 36% humidity for 20 h to evaluate any change in the water content and thus its hygroscopicity.
  • the change in the total weight of amorphous eliglustat hemitartrate found 0.02%, indicating a low degree of hygroscopicity.
  • Residual solvent content (toluene): 0.01wt%.

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Abstract

Process for preparation of eliglustat hemitartrate and intermediates thereof Processes for preparation of eliglustat hemitartrate and intermediates thereof are provided. A stable amorphous form of eliglustat hemitartrate pharmaceutical compositions including the amorphous form of eliglustat hemitartrate, and their uses are also provided.

Description

Process for preparation of eliglustat hemitartrate and intermediates thereof
FIELD
The present disclosure relates to a novel process for the preparation of eliglustat hemitartrate and intermediates thereof. The present disclosure also relates to stable amorphous form of eliglustat hemitartrate, process for its preparation and pharmaceutical composition thereof.
BACKGROUND
Eliglustat tartrate is chemically described as N-((lR,2R)-l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-l-hydroxy-3-(pyrrolidin-l-yl)propan-2-yl) octanamide (2R,3R)-2,3-dihydroxysuccinate and is marketed as Cerdelga® by Genzyme Corp. for the long term treatment of adult patients with Gaucher disease type 1. Eliglustat hemitartrate has the structure of formula (I).
Figure imgf000003_0001
(I)
U.S. Patent No. 7,196,205 (herein, "the '205 patent") discloses a process for the preparation of eliglustat as shown in scheme-I. In the process of '205 patent, phenyl-a- bromoacetate is reacted with S-(+)-phenyl glycinol to provide (5S)-5-phenylmorpholin-2-one, which is condensed with benzodioxolane-6-carboxaldehyde to provide (lR,3S,5S,8aS)-l,3-bis- (2',3'-dihydro-benzo[l,4]dioxin-6'-yl)-5-phenyl-tetrahydro-oxazolo[4,3-c][l,4]oxazin-8-one. The resulting cycloadduct compound is reacted with pyrrolidine followed by methanol and aqueous hydrochloric acid solution to provide (2S,3R,l"S)-3-(2',3'-dihydro-benzo[l,4]dioxin-6'-yl)-3- hydroxy-2-(2"-hydroxy-l"-phenyl-ethylamino)-l-pyrrolidin-l-yl-propan-l-one, which is further reduced with lithium aluminum hydride and debenzylated with 20% palladium hydroxide on carbon to yield (lR,2R)-2-amino-l-(2',3'-dihydro-benzo[l,4]dioxin-6'-yl)-3-pyrrolidin-l-yl- propan-l-ol. The final step involves condensation of the resulting product with octanoic acid N- hydroxysuccinimide ester to yield eliglustat.
Figure imgf000004_0001
Scheme-I
CN105646442A discloses reaction of (lR,2R)-2-amino- dihydrobenzo[b][l,4]dioxin-6-yl)-3-(pyrrolidin-l-yl)propan-l-ol with boc anhydride followed by benzyl bromide and then de-protection of the boc group to provide (lR,2R)-l-(benzyloxy)-l- (2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-3-(pyrrolidin-l-yl)propan-2-amine. Condensation of the resulting compound with octanoyl chloride yields benzylated eliglustat which is debenzylated by hydrogenation to provide eliglustat.
Figure imgf000004_0002
Scheme-II
U.S. Patent No. 6,916,802 discloses a process for preparing ceramide-like compounds which involves resolution of isomers by chromatography. However, this process is not suitable for large scale industrial preparations. Therefore, there is a need to develop a simple iterative process for the preparation of eliglustat and its tartrate salt which is economical and applicable on an industrial scale.
U.S. Patent Application Publication No. 2013/137743 discloses crystalline form A of eliglustat hemitartrate and a process for preparation thereof.
Amorphous eliglustat hemitartrate is known from WO2016/001885 and IN201621009771, in which the amorphous eliglustat hemitartrate is obtained by spray drying or by dissolving eliglustat hemitartrate in a solvent or a mixture of solvent, followed by evaporation under reduced pressure to obtain solid residue. The said process is not suitable for industrial application as the residue obtained has a higher amount of residual solvent. Moreover, the obtained amorphous material is not stable and is hygroscopic in nature, and therefore is not suitable in handling and use for pharmaceutical developments.
Therefore, there is a need to provide a process for the preparation of stable amorphous eliglustat hemitartrate which is substantially free from residual solvent, industrially scalable for bulk manufacturing, and stable at least at ordinary storage conditions.
The present inventors have found that the amorphous eliglustat hemitartrate obtained herein is non-hygroscopic, substantially free from residual solvent, industrially scalable for bulk manufacturing and stable towards polymorphic conversion at ambient conditions. One or more embodiments provide a simple and commercially advantageous process for the preparation of amorphous eliglustat hemitartrate.
SUMMARY
The present invention provides processes for the preparation of eliglustat or its tartrate salt (I). Also provided are: a stable amorphous form of eliglustat hemitartrate, a process for preparation thereof, a pharmaceutical composition comprising the same, and use of eliglustat hemitartrate for treatment of gaucher disease.
In one aspect, a process for preparation of eliglustat or its tartrate salt comprises:
(a) reacting racemic eliglustat of formula (VII)
Figure imgf000005_0001
(VII) with a chiral acid in the presence of a suitable solvent to provide a chiral acid salt; optionally purifying the chiral acid salt;
(b) reacting the chiral acid salt with a suitable base to provide eliglustat free base of formula (IX)
Figure imgf000006_0001
optionally purifying the eliglustat free base in a suitable solvent; and
(c) optionally reacting the eliglustat free base of formula (IX) with L-(+)-tartaric acid in the presence of a suitable solvent to provide eliglustat tartrate, preferably eliglustat hemitartrate (I).
In another aspect, a process for preparation of eliglustat or its tartrate salt comprises: (a) reacting racemic eliglustat of formula II)
Figure imgf000006_0002
with di-p-toluoyl-D-tartaric acid in the presence of a suitable solvent to provide di-p- toluoyl-D-tartrate salt of formula (VIII); optionally purifying the di-p-toluoyl-D-tartrate salt of formula (VIII);
Figure imgf000006_0003
(VTTT)
(b) reacting the eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) with a suitable base to provide eliglustat free base of formula (IX)
Figure imgf000006_0004
(IX) optionally purifying the eliglustat of formula (IX) in a suitable solvent; and (c) optionally reacting the eliglustat of formula (IX) with L-(+) -tartaric acid in the presence of a suitable solvent to provide eliglustat tartrate, preferably eliglustat hemitartrate (I).
In yet another aspect, a process for preparation of racemic eliglustat of formula (VII) comprises:
(a) reacting 2,3-dihydrobenzo [l,4]dioxine of formula (II)
Figure imgf000007_0001
(Π)
with chloroacetyl chloride to provide 2-chloro-l-(2,3-dihydrobenzo[b][l,4]dioxin-6- yl)ethan-l-one of formula (III) which is in situ reacted with an aminating agent and hydrochloric acid to provide a hydrochloride salt of 2-amino-l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl ethan-l-one of formula (IV)
Figure imgf000007_0002
(b) reacting the compound of formula (IV) with octanoic acid or one or more derivatives thereof in the presence of a suitable solvent to provide N-(2-(2,3- dihydrobenzo[b][l,4]dioxin-6- -2-oxoethyl)octanamide of formula (V)
Figure imgf000007_0003
(V)
(c) reacting the compound of formula (V) with paraformaldehyde and pyrrolidine to provide N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l-yl)propan-2- yl)octanamide of formula (VI); optionally treating the compound of formula (VI) with oxalic acid in the presence of a suitable sol ent to provide an oxalate salt of formula (VI)
Figure imgf000007_0004
(VI) Oxalate (d) reacting the compound of formula (VI) or its oxalate salt with a suitable reducing agent to provide racemic eliglustat of formula (VII)
Figure imgf000008_0001
In yet another aspect, eli lustat di-p-toluoyl-D-tartrate salt of formula (VIII)
Figure imgf000008_0002
(Vlll)
is directly converted to eliglustat hemitartrate of formula (I) without isolating the eliglustat free base of formula (IX).
In yet another aspect, a process for recycling racemic eliglustat of formula (VII) or its salt, comprises:
(a) reacting mother liquor obtained after isolation of eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII)
Figure imgf000008_0003
(Vlll)
with an oxidizing agent followed by epimerization to provide a compound of formula (VI), optionally treating the com ound of formula (VI)
Figure imgf000008_0004
(VI)
with oxalic acid in the presence of a suitable solvent to provide an oxalate salt of formula (VI); and
(b) reducing the compound of formula (VI) or its oxalate salt to provide a racemic eliglustat of formula (VII)
Figure imgf000009_0001
(VII)
In yet another aspect, eliglustat or its salt is prepared substantially free of impurity eliglustat N-oxide of formula (X)
Figure imgf000009_0002
(X)
In yet another aspect, provided are novel intermediates: N-(2-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-2-oxoethyl)octan-amide of formula (V); N-(l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l-yl)propan-2-yl)octanamide of formula (VI); oxalate salt of N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l- yl)propan-2-yl)octanamide of formula (VI); and di-p-toluoyl-D-tartrate salt of eliglustat of formula (VIII), and their pharmaceutically acceptable solvates and hydrates thereof; processes for their preparation; and their uses for the preparation of eliglustat or tartrate salts thereof.
In yet another aspect, provided is a stable amorphous form of eliglustat hemitartrate of formula (I)
Figure imgf000009_0003
(I)
In yet another aspect, a process for preparation of stable amorphous eliglustat hemitartrate comprises:
(a) suspending eliglustat hemitartrate in a suitable solvent and removing the solvent to obtain a residue;
(b) adding a suitable solvent to the residue; and
(c) obtaining the amorphous form of eliglustat hemitartrate. In yet another aspect, the stable amorphous form of eliglustat hemitartrate is characterized by X-ray powder diffraction as depicted in Fig. 1 and/or Fig. 2.
In yet another aspect, a pharmaceutical composition comprises the stable amorphous form of eliglustat hemitartrate together with one or more pharmaceutically acceptable carriers, excipients or diluents.
In yet another aspect, stable amorphous eliglustat hemitartrate is used for treatment of Gaucher disease.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1: The X-ray diffraction pattern of stable amorphous eliglustat hemitartrate obtained after drying at about 50-55° C for about 4-6 hours under reduced pressure.
Fig. 2: The X-ray diffraction pattern of stable amorphous eliglustat hemitartrate after 1 month storage at ambient temperature.
DETAILED DESCRIPTION
The term "Lewis acid" is used herein to refer to a substance which can accept an unshared electron pair from another molecule.
The term "about", as used herein, means a variation of up to 10% from such values, or in case of a range of values, means up to a 10% variation from both the lower and upper limits of such ranges.
The term "ambient temperature", as used herein, refers to a temperature in the range of about 20° C to about 35° C.
"Suitable solvent" means a single or a combination of two or more solvents.
As used herein, the term "obtaining" means isolating by way of filtration, filtration under vacuum, centrifugation, decantation and the like. The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be dried in a tray drier, dried under vacuum and/or in a fluid bed drier.
The term "tartrate salt" as used herein covers monotartrate and hemitartrate.
In one aspect, a process for preparation of eliglustat or its tartrate salt, comprises:
(a) reacting racemic eliglustat of formula (VII)
Figure imgf000011_0001
(VII)
with a chiral acid in presence of a suitable solvent to provide a chiral acid salt; optionally purifying the chiral acid salt;
(b) reacting the chiral acid salt with a suitable base to provide eliglustat free base of formula (IX)
Figure imgf000011_0002
(IX)
optionally purifying the eliglustat free base in a suitable solvent; and
(c) optionally reacting the eliglustat free base of formula (IX) with L-(+)-tartaric acid in the presence of a suitable solvent to provide eliglustat tartrate, preferably eliglustat hemitartrate (I).
The resolution solvent may be a solvent or solvent mixture in which the racemic eliglustat and chiral acid are soluble, either completely or partially. Solvents that may be used for salt formation include, but are not limited to, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol and the like; halogenated hydrocarbons such as dichloromethane, chlorobenzene, chloroform and the like or mixtures thereof.
Chiral acids can be used for resolution, which facilitates the synthesis of desired enantiomers with absolute configurational assignment. Suitable chiral acids include any optically enriched chiral acid capable of forming an isolable salt with racemic eliglustat of formula (VIII). Non-limiting examples of chiral acids include one or more of: mandelic acid, malic acid, camphor sulfonic acid, di-p-toluoyl-D-tartaric acid, di-m-toluoyl-D-tartaric acid, and di-benzoyl- D-tartaric acid. Preferably, di-0,0'-aroyl-D- or L-tartaric acid can be used as a chiral acid to resolve racemic eliglustat of formula (VII). More preferably, the chiral acid is di-p-toluoyl-D- tartaric acid. Suitable bases include any base, either organic or inorganic, which allow release of the eliglustat free base from its salt form. Bases include, but are not limited to, alkali or alkaline earth metal carbonates such as: sodium carbonate, potassium carbonate; bicarbonate such as sodium bicarbonate, potassium bicarbonate; and hydroxide such as sodium hydroxide, potassium hydroxide; or mixtures thereof.
In another aspect, a process for preparation of eliglustat or its tartrate salt comprises the steps of:
(a) reacting racemic eliglustat of formula VII)
Figure imgf000012_0001
(VII)
with di-p-toluoyl-D-tartaric acid in the presence of a suitable solvent to provide di-p- toluoyl-D-tartrate salt of formula (VIII); optionally purifying the di-p-toluoyl-D-tartrate salt of formula (VIII)
Figure imgf000012_0002
(VTTT)
(b) reacting the eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) with a suitable base to provide eliglustat free base of formula (IX)
Figure imgf000012_0003
(IX)
optionally purifying the eliglustat of formula (IX) in a suitable solvent; and
(c) optionally reacting the eliglustat of formula (IX) with L-(+) -tartaric acid in the presence of a suitable solvent to provide eliglustat tartrate, preferably eliglustat hemitartrate (I).
In (a), racemic eliglustat of formula (VII) is reacted with di-p-toluoyl-D-tartaric acid in the presence of a suitable solvent to provide di-p-toluoyl-D-tartrate salt of formula (VIII). Solvents that may be used for salt formation include, but are not limited to: alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol and the like; and halogenated hydrocarbons such as dichloromethane, chlorobenzene, chloroform and the like; or mixtures thereof. Eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) may be purified from solvents selected from, but not limited to, alcohols such as methanol, ethanol, isopropanol and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like; polar aprotic solvents such as dimethylformamide, acetamide and the like; ethers such as tetrahydrofuran, methyl tert. butyl ether and the like; and water; or mixtures thereof.
In (b), eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) is reacted with a suitable base in the presence of a solvent to provide eliglustat free base of formula (IX). Solvents include, but are not limited to: halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chlorobenzene, chloroform and the like; hydrocarbons such as toluene, xylene and the like; and water; or mixtures thereof. Bases include, but are not limited to: alkali or alkaline earth metal carbonate such as sodium carbonate, potassium carbonate; bicarbonate such as sodium bicarbonate, potassium bicarbonate; and hydroxide such as sodium hydroxide, potassium hydroxide; or mixtures thereof. Preferably, the reaction may be carried out with dichloromethane, water and potassium carbonate to provide eliglustat free base of formula (IX). Eliglustat free base of formula (IX) may be purified from solvents selected from, but not limited to: hydrocarbons such as toluene, xylene, hexane, heptane, cyclohexane and the like; polar aprotic solvents such as dimethylformamide, acetamide and the like; ethers such as tetrahydrofuran, methyl tert. butyl ether and the like; and water; or mixtures thereof.
In (c), eliglustat free base of formula (IX) is reacted with L-(+)-tartaric acid in the presence of a suitable solvent to provide eliglustat tartrate, preferably eliglustat hemitartrate (I). Solvents include, but are not limited to: hydrocarbons such as toluene, xylene and the like; alcohols such methanol, ethanol, isopropanol and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; and water; or mixtures thereof. Preferably, the reaction may be carried out with toluene, water and L-(+)-tartaric acid to provide eliglustat hemitartrate (I). The reaction may be carried out at a temperature of about 10° C to about 130° C, preferably at about 20° C to about 80° C. The reaction of eliglustat free base of formula (IX) with L-(+)-tartaric acid may be carried out for about 15 min. to about 4 hours, preferably for about 30 min. to about 2 hours. Eliglustat hemitartrate of formula (I) may be isolated from the reaction mixture by evaporation, filtration, concentration, precipitation, cooling, centrifugation, decantation or any other suitable technique known in the art. Eliglustat hemitartrate of formula (I) may be isolated from the reaction mixture using solvent. Solvent used for isolation may include, but are not limited to: hydrocarbons such as toluene, xylene, hexane, heptane, cyclohexane and the like; and water; or mixtures thereof.
In yet another aspect, a process for preparation of racemic eliglustat of formula (VII) comprises:
(a) reacting 2,3-dihydrobenzo [l,4]dioxine of formula (II)
Figure imgf000014_0001
(Π)
with chloroacetyl chloride to provide 2-chloro-l-(2,3-dihydrobenzo[b][l,4]dioxin-6- yl)ethan-l-one of formula (III) which is in situ reacted with an aminating agent and hydrochloric acid to provide a hydrochloride salt of 2-amino-l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)ethan-l-one of formula (IV)
Figure imgf000014_0002
(IV)
(b) reacting the compound of formula (IV) with octanoic acid or one or more derivatives thereof in the presence of a suitable solvent to provide N-(2-(2,3- dihydrobenzo[b][l,4]dioxin-6- -2-oxoethyl)octanamide of formula (V)
Figure imgf000014_0003
(V)
(c) reacting the compound of formula (V) with paraformaldehyde and pyrrolidine to provide N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l-yl)propan-2- yl)octanamide of formula VI); optionally treating the compound of formula (VI)
Figure imgf000014_0004
(VI) Oxalate
with oxalic acid in the presence of a suitable solvent to provide an oxalate salt of formula (VI); and (d) reacting the compound of formula (VI) or its oxalate salt with a suitable reducing agent to provide racemic eliglustat of formula (VII)
Figure imgf000015_0001
(VII)
In (a), there is Friedel-Crafts acylation of 2,3-dihydrobenzo [l,4]dioxine of formula (II) with chloroacetyl chloride using suitable solvent and Lewis acid to provide 2-chloro-l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)ethan-l-one of formula (III). Lewis acids that may be used for include, but are not limited to: aluminum trichloride (AICI3), aluminum tribromide (AlBr3), boron trifluoride, zinc chloride and the like. The obtained compound of formula (III) is in situ reacted with an aminating agent and hydrochloric acid to provide 2-amino-l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)ethan-l-one hydrochloride of formula (IV). Aminating agents that may be used include, but are not limited to: hexamine, ammonia and the like. Solvents that may be used include, but are not limited to: halogenated hydrocarbons such as dichloromethane, chlorobenzene, chloroform and the like; hydrocarbon such as toluene, xylene and the like; or mixtures thereof.
In (b), there is condensation of 2-amino-l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)ethan-l- one hydrochloride of formula (IV) with octanoic acid or one or more derivatives thereof in the presence of a suitable solvent to provide N-(2-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-2- oxoethyl)octanamide of formula (V). Non-limiting examples of the octanoic acid derivatives include: corresponding octanoyl halide, symmetric or mixed carboxylic anhydride, and the corresponding sulfonyloxy or imidazole derivatives. The reaction can be carried out using condensing agents such as CDI (carbonyldiimidizole), HOBt (1-hydroxybenzotriazole), HATU ((0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate)), TATU ((0- (7-azabenzotriazole-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate)), EDC (l-ethyl-3-(3- dimethylaminopropyl)carbodiimide), and DCC (Ν,Ν'-dicyclohexylcarbodiimide) in organic solvent, optionally in the presence of a base. Solvents that may be used include, but are not limited to: halogenated hydrocarbons such as dichloromethane, chlorobenzene, chloroform and the like; hydrocarbon such as toluene, xylene and the like; and ethers such as tetrahydrofuran (THF) and diethyl ether; or mixtures thereof. Bases that may be used include, but are not limited to: diisopropylethylamine (DIPEA), triethylamine (TEA), diethylamine (DEA), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), imidazole, Ν,Ν-dimethyl aniline, 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), potassium carbonate, sodium carbonate, and the like. The acetylation of formula (IV) may be performed in the presence of a catalyst. Examples of catalysts include, but are not limited to: Ν,Ν-dimethyl aminopyridine (DMAP), N-methyl piperazine (NMP), and the like.
In (c),there is Mannich condensation of N-(2-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-2- oxoethyl)octanamide of formula (V) with paraformaldehyde and pyrrolidine in the presence of a solvent to provide N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l-yl)propan- 2-yl)octanamide of formula (VI). Solvents that may be used include, but are not limited to: hydrocarbon such as toluene, xylene, or mixtures thereof. Optionally, compound of formula (VI) is treated with oxalic acid in the presence of a suitable solvent to provide oxalate salt of formula (VI). Solvents that may be used for salt formation include, but are not limited to: alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, or mixtures thereof.
In (d),there is reduction of N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3- (pyrrolidin-l-yl)propan-2-yl)octanamide of formula (VI) or its oxalate salt with a suitable reducing agent to provide racemic eliglustat of formula (VII). Reduction of the ketone group of compound of formula (VI) or its oxalate salt predominantly provides R isomer. Solvents that may be used for reduction include, but are not limited to: alcohols such as methanol, ethanol, n- propanol, isopropanol, n-butanol, and t-butanol, or mixtures thereof. Reduction can be performed by catalytic hydrogenation or with a hydrogenation reducing agent. Examples of a catalytic hydrogenation reducing agent may include: noble metal catalyst such as Pd, Pt, Rh and Ru supported on carbon, or using a complex of such metal such as palladium, palladium-carbon, palladium hydroxide-carbon, platinum oxide, copper chromite, palladium acetate, platinum- carbon, palladium-alumina, and Raney nickel. These catalytic hydrogenation reducing agents are used singly or in combination of two or more types. Examples of a hydrogenation reducing agent may include: sulfite compounds such as sodium bisulfite, sodium sulfite, sodium pyrosulfite, ammonium sulfite, ammonium sulfite monohydrate, or ammonium bisulfite; tetra lower alkyl ammonium borohydrides such as tetra methyl ammonium borohydride, tetra ethyl ammonium borohydride, tetra-n-butyl ammonium borohydride, tetra-n-butyl ammonium cyanoborohydride, sodium cyanoborohydride, lithium cyanoborohydride, sodium borohydride, potassium borohydride, lithium aluminum hydride and diborane. In yet another aspect, eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) is directly converted to eliglustat hemitartrate of formula (I) without isolating the eliglustat free base of formula (IX). In this process, eliglustat free base of formula (IX) is not isolated but rather converted in situ to the eliglustat hemitartrate of formula (I). Eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) is reacted with a suitable base in the presence of a solvent to provide eliglustat free base of formula (IX), which was in situ reacted with L-(+)-tartaric acid in the presence of a suitable solvent to provide eliglustat tartrate, preferably eliglustat hemitartrate of formula (I). This involves an in situ cost-effective process for the preparation of eliglustat hemitartrate of formula (I).
Figure imgf000017_0001
L(+ Tartaric acid
Figure imgf000017_0002
Eliglustate hemitartrate
In order to minimize material loss, the undesired isomer of eliglustat can be recovered from the mother liquors of the resolution step by oxidation, followed by epimerization and reduction to provide racemic eliglustat, which can be recycled for further resolution.
In yet another aspect, a process for recycling racemic eliglustat of formula (VII) or its salt, comprises:
(a) reacting mother liquor obtained after isolation of eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII)
Figure imgf000017_0003
(Will)
with an oxidizing agent followed by epimerization to provide a compound of formula (VI) , optionally treating the compound of formula (VI)
Figure imgf000018_0001
(VI)
with oxalic acid in the presence of a suitable solvent to provide an oxalate salt of formula (VI); and
(b) reducing the compound of formula (VI) or its oxalate salt to provide racemic eliglustat of formula (VII)
Figure imgf000018_0002
(VII)
The mother liquor obtained after the isolation of the desired eliglustat di-p-toluoyl-D- tartrate salt of formula (VIII) may be oxidized by oxidizing agent such as potassium dichromate, potassium permanganate, hydrogen peroxide, sodium hypochlorite, sodium hypobromite, chromium trioxide in dilute sulfuric acid, mixture of potassium dichromate and dilute sulfuric acid, Jones oxidation, Swern oxidation, Baeyer-Villiger oxidation, Oppenauer oxidation, and Pinnick oxidation, or mixtures thereof. Oxidation may be carried out in the presence of a solvent such as: ketone, ether, and a halogenated hydrocarbon, or mixtures thereof. The obtained compound of formula (VI) may be epimerized in the presence or absence of base. Reduction of N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l-yl)propan-2-yl)octanamide of formula (VI) or its oxalate salt may carried out as described above.
1 . Oxidation
2. Epimerization
Mother liquer of (VIII)
Di-para toluoyl
D-tartaric acid
Methanol
Figure imgf000018_0003
In yet another aspect, eliglustat or its salt is prepared having a relatively low content of one or more organic impurities compared to known organic impurities in the art. A content of eliglustat N-oxide impurity of formula (X) can be controlled to a minimum level by in situ reacting the eliglustat base of formula (IX) with tartaric acid and thereby obtaining eliglustat hemitartrate salt substantially free from eli lustat N-oxide impurity of formula (X)
Figure imgf000019_0001
(X)
In yet another aspect, provided are novel intermediates: N-(2-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-2-oxoethyl) octanamide of formula (V); N-(l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l-yl)propan-2-yl)octanamide of formula (VI); oxalate salt of N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l- yl)propan-2-yl) octanamide of formula (VI); and di-p-toluoyl-D-tartrate salt of eliglustat of formula (VIII), and their pharmaceutically acceptable solvates and hydrates thereof; processes for their preparation; and their uses for the preparation of eliglustat or tartrate salts thereof.
In yet another aspect, provided is a stable amorphous form of eliglustat hemitartrate of formula (I)
Figure imgf000019_0002
(I)
The amorphous eliglustat hemitartrate is non-hygroscopic and does not convert into crystalline form at ambient temperature. Also, amorphous eliglustat hemitartrate, as described herein, is stable against thermal degradation during drying at elevated temperature.
In an embodiment, the amorphous eliglustat hemitartrate is non-hygroscopic. In an embodiment, upon exposure to an atmosphere of about 36% humidity for a period of 20 hours, the change in the total weight of amorphous eliglustat hemitartrate was found to be about 0.02 weight percent. Thus, the amorphous eliglustat hemitartrate may be characterized by such non- hygroscopicity upon exposure to an atmosphere of about 36% humidity for a period of 20 hours. This non-hygroscopic nature of the amorphous eliglustat hemitartrate renders it exceptionally suitable for use in preparing pharmaceutical compositions.
According to another embodiment, the stable amorphous eliglustat hemitartrate refers to an amorphous form of eliglustat hemitartrate that remains stable towards conversion to crystalline form at ambient temperature for a period of at least 1 month, showing no change in polymorphic form by X-ray powder diffraction when placed at a temperature of 25 ±2° C at a relative humidity of 60 +5% for 1 month, or at a temperature of 5 ±2° C for 1 month.
According to another embodiment, the stable amorphous eliglustat hemitartrate is substantially free of residual solvent, wherein the term "substantially free of residual solvent" refers to the stable amorphous form of eliglustat hemitartrate having less than 5000 ppm of residual solvent.
In yet another aspect, a process for preparation of stable amorphous eliglustat hemitartrate comprises :
(a) providing a suspension of eliglustat hemitartrate in a suitable solvent and removing the solvent to obtain residue;
(b) adding a suitable solvent to the residue; and
(c) obtaining the amorphous form of eliglustat hemitartrate.
The starting material to be used for the preparation of stable amorphous eliglustat hemitartrate can be obtained by a method known to a person of ordinary skill in the art including, for example, the method described in WO 2016/001885 and/or US Publication No. 2013/0137743, which are incorporated herein by reference.
The suspension of eliglustat hemitartarate can be obtained by known methods that include direct use of a reaction mixture containing eliglustat hemitartarate that is obtained in the course of its synthesis, or suspension of eliglustat hemitartarate in suitable solvent or mixture of solvents.
The suspension of eliglustat hemitartrate may be a clear solution with homogenous mixture or a suspension or slurry with a heterogeneous mixture in suitable solvent. Suitable solvent may include, but is not limited to,: hydrocarbons such as toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene and the like; alcohols such as methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol and the like; ketones such as acetone, butanone, 2-pentanone, 3- pentanone, methyl butyl ketone, methyl isobutyl ketone and the like; esters such as methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate and the like; nitriles such as acetonitrile and the like; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol and the like; and polar aprotic solvents such as N,N-dimethylformamide, Ν,Ν-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane and the like; or mixtures thereof.
In (a), solvent is removed to obtain a residue. The suspension of eliglustat hemitartrate in solvent may be distilled until partial removal of solvent by distillation under vacuum.
Suitable techniques that can be used for the removal of solvent include but not limited to: evaporation, simple evaporation, decantation, and rotational drying, or any other suitable technique known in the art.
The solvent may be removed, optionally under reduced pressures, at temperature less than about 150° C, less than about 100° C, less than about 75° C, less than about 50° C, or any other suitable temperature.
In an embodiment, eliglustat hemitartrate is suspended in toluene under reflux conditions and the water contained in it is removed by azeotropic distillation.
The solvents of (b) include but are not limited to a group of solvents in which eliglustat hemitartrate is insoluble or poorly soluble or partially soluble. The solvents may include, but are not limited to: ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol and the like; and hydrocarbons such as toluene, xylene, hexane, cyclohexane, heptane and the like; or mixtures thereof.
Embodiments of the process may further comprise dissolving the obtained eliglustat hemitartrate in solvent and removing the solvent to obtain a residue. The residue is treated with suitable solvent to obtain an amorphous form of eliglustat hemitartrate.
In (c), an amorphous form of eliglustat hemitartrate is obtained. The isolation may be effected by removing the solvent. Suitable techniques which can be used for the removal of solvent include but are not limited to filtration, decantation or any other suitable technique known in the art.
In an embodiment, suitable techniques which can be used for obtaining an amorphous form of eliglustat hemitartrate include, but not limited to, filtration under vacuum, evaporation, decantation or any other suitable technique known in the art.
The obtained amorphous eliglustat hemitartrate from (c) may be collected by using techniques such as by scraping or by shaking the container or other techniques specific to the equipment used. The isolated solid may be optionally further dried to afford an amorphous form of eliglustat hemitartrate. Drying can be carried out under reduced pressure, vacuum tray drying or air drying. Drying can be carried out for any desired times until the required product quality is achieved.
The obtained eliglustat hemitartrate may be dried under vacuum at about 50° C to 70° C for 6-12 hours to obtain the amorphous form substantially free from residual solvent. The obtained amorphous eliglustat hemitartrate is stable under ordinary stability conditions at least for 1 month and does not change to crystalline form.
In yet another aspect, the stable amorphous form of eliglustat hemitartrate is characterized by the X-ray powder diffraction substantially as depicted in Fig. 1 and/or Fig. 2.
In yet another aspect, a pharmaceutical composition comprises the stable amorphous form of eliglustat hemitartrate together with one or more pharmaceutically acceptable carriers or excipients.
Pharmaceutical compositions containing stable amorphous eliglustat hemitartrate may be prepared by using excipients such as diluents, binders, wetting agents, disintegrating agents, surface active agents and lubricants. Various modes of administration of the pharmaceutical compositions of the invention may be selected depending on the therapeutic purpose for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories or injection preparations.
In yet another aspect, use of stable amorphous eliglustat hemitartrate is for treatment of Gaucher disease. The pharmaceutical compositions containing stable amorphous eliglustat hemitartrate disclosed herein can be used for treatment of Gaucher disease.
The HPLC purity of eliglustat hemitartrate was determined using a symmetry CI 8 (250* 4.6mm, 5μιη) column with a flow rate of 1.2 ml/min; column oven temperature: 40° C; sample tray temperature: ambient; detector: UV at 275nm; injection volume: 20μ1; runtime: 65 min.
All PXRD data reported herein were obtained using Cu K-a radiation having the wavelength 1.541 A using a PanAlytical, Powder X-ray Diffractometer.
In one embodiment, the synthetic reaction scheme for eliglustat hemitartrate is as shown in Scheme-Ill. Hexamine O
Dichloromethane •NH2 HC1
Isopropyl alcohol
Figure imgf000023_0001
Dichloromethane Con. HC1 (IV)
(Π) (III) 1-Octanoyl chloride
Triethylamine
Dichloromethane
Figure imgf000023_0002
Isopropyl alcohol
Toluene
Sodium borohydride
Methanol
Figure imgf000023_0003
Scheme-Ill
In another embodiment, the synthetic reaction scheme for eliglustat hemitartrate is shown in Scheme-IV.
,
Figure imgf000024_0001
Isopropyl alcohol
(VI) Oxalate Toluene (V)
Sodium borohydride
Methanol
Figure imgf000024_0002
Eliglustate hemitartrate Eliglustat
Scheme-IV
The following examples are given for the purpose of illustrating the present invention and should not be considered as limiting the scope of the invention.
EXAMPLES
Example-1: Preparation of 2-amino-l-(2, 3-dihydrobenzo[b][l,4]dioxin-6-yl)ethan-l-one hydrochloride (IV)
To a stirred solution of anhydrous aluminium chloride (108.0 g) in dichloromethane (2100 ml), a solution of chloroacetyl chloride (83.0 g) in dichloromethane (200 ml) was added under nitrogen atmosphere at 10-20°C and stirred for 15 min. Then a solution of 1,4-benzodioxan (100.0 g) in dichloromethane (200 ml) was added slowly to the reaction mixture at 10-20° C and stirred for 1 h. After completion of reaction, the reaction mixture was quenched into dilute hydrochloric acid solution (1500 ml) at 20-35° C, stirred for 1 h and allowed to settle. Organic layer was separated and washed with water (500 ml). Hexamine (113.0 g) was added to the obtained organic layer and heated to reflux for 10 h. After completion of reaction, the reaction mixture was cooled to 5- 15° C and stirred for 1 h. The precipitated solid was filtered, washed with cold dichloromethane (100 ml X 2) and the product sucked dry. The obtained wet cake was added in to a stirred solution of isopropyl alcohol (600 ml) and hydrochloric acid (300 ml). The reaction mixture was heated to 40-50° C and stirred for 7 h. After completion of the reaction, the reaction mixture was cooled to 5-15° C and stirred for 120 min. The solid was filtered and washed with cold isopropyl alcohol (100 ml X 2). The product was sucked dry and then dried at 60-70° C to give the title product (172.0 g).
1H NMR (DMSO-d6)5: 4.30-4.32 (2H, m), 4.34-4.37 (2H, m), 4.49 (2H, s), 7.03-7.05 (1H, d), 7.52-7.53 (1H, d), 7.54-7.56 (1H, dd), 8.37 (3H, bs).
Mass: 194.1 [M+H] +
Example 2: Preparation of N-(2-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-2- oxoethyl)octanamide (V)
To a stirred mixture of 2-amino-l-(2,3-dihydrobenzo [b] [l,4]dioxin-6-yl)ethan-l-one hydrochloride (100.0 g), 1-octanoyl chloride (92.5 g) and dichloromethane (1000 ml), a solution of triethylamine (110.0 g) in dichloromethane (500 ml) was added under nitrogen atmosphere at
0- 10° C. The reaction mixture was allowed to warm at 25-30° C and stirred for 2 h. After completion of the reaction, water (1000 ml) was added to the reaction mixture and stirred for 30 min. The layers were separated and the organic layer washed with saturated aqueous sodium bicarbonate solution (500 ml). The organic layer was distilled out under vacuum to get residue. The residue was azeotroped with isopropyl alcohol (100 ml) and then degased for 20 min. To the obtained crude product was added isopropyl alcohol (300 ml) and stirred at 75-85° C for 30 min. The reaction mixture was cooled at 20-30° C and stirred for 1 h. The solid was filtered and washed with isopropyl alcohol (50 ml X 2). The solid was dried at 50-60° C to give the title product (118.0 g).
1H NMR (CDC13)5: 0.86-0.89 (3H, t), 1.26-1.35 (8H, m), 1.61-1.71 (2H, m), 2.27-2.31 (2H, t), 4.28-4.30 (2H, m), 4.32-4.34 (2H, m), 4.67-4.68 (2H, d), 6.54(1H, bs), 6.92-6.94 (1H, d), 7.50 (1H, d), 7.52 (lH, s).
Mass: 320.2 [M+H] +
Example 3: Preparation of N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-
1- yl)propan-2-yl)octanamide oxalate (VI) To a stirred mixture of paraformaldehyde (12.2 g) and pyrrolidine (29.0 g) in toluene (700 ml), N-(2-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-2-oxoethyl)octanamide (100.0 g) was added under nitrogen atmosphere at 25-30° C and stirred for 10 min. The reaction mixture was heated to 55- 65° C and stirred for 6 h. After completion of the reaction, the reaction mixture was cooled to 25-30° C and washed with water (500 ml). The organic layer was separated, and a solution of oxalic acid dihydrate (39.5 g) in isopropyl alcohol (200 ml) was added to the organic layer. The reaction mixture was stirred at 25-30° C for 1 h and at 0-10° C for 2 h. The solid was filtered and washed with toluene (100 ml X 2). The solid was dried at 25-35°C for 2 h and then at 45-55° C for 8 h to give the title product (113.85 g).
1H NMR (DMSO-d6)5: 0.81-0.84 (3H, t), 1.03-1.22 (8H, m), 1.37-1.41 (2H, m), 1.82-1.86 (6H, m), 2.01-2.13 (2H, m), 3.08-3.37(4H, m), 4.27-4.33 (4H, m), 5.46-5.51 (1H, m), 6.96-6.98(lH, d), 7.43-7.48 (2H, d), 8.58-8.60 (1H, d).
Mass: 403.4 [M+H] +
Example 4: Preparation of N-((lR,2R)-l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-hydroxy- 3-(pyrrolidin-l-yl)propan-2-yl)octanamide di-p-tolyl-D-tartrate (VIII)
To a stirred mixture of N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l- yl)propan-2-yl) octanamide oxalate (100.0 g) and methanol (700 ml), sodium borohydride (9.6 g) was added in 10 equal lots with 10 minute intervals at -20 to -10° C . The reaction mixture was stirred for 1 h. After completion of the reaction, the reaction mixture was quenched with dilute hydrochloric acid (37 ml) solution in 40 ml water within 30 min. The reaction mixture was allowed to warm at 25-35° C and then water (700 ml) and dichloromethane (700 ml) were added to the reaction mixture. The pH of the reaction mixture was adjusted to 8.0-10.0 with 20% potassium carbonate solution. The reaction mixture was stirred for 30 min. and then the layers were separated. The organic layer was washed with water (200 ml), distilled out under vacuum and then azeotroped with methanol (100 ml). The obtained crude product (VII) was dissolved in methanol (700 ml), and then a solution of di-p-tolyl-D-tartaric acid (74.5 g) in methanol (300 ml) was added at 50-60° C. The reaction mixture was stirred at 50-60° C for 1 h. Then the reaction mixture was cooled at 25-35° C and stirred for 2 h. The solid was filtered and washed with methanol (50 ml X 2). Suck dry and mixed the obtained wet cake with methanol (750 ml). The reaction mixture was heated to reflux for 1 h, then the reaction mixture was cooled at 25-35° C and stirred for 2 h. The solid was filtered and washed with methanol (50 ml X 2). The solid was dried at 25-35° C for 2 h and then at 55-65° C for 8 h to give the title product (43.32 g). 1H NMR (DMSO-d6)5: 0.83-0.87 (3H, t), 0.99-1.02 (2H, m), 1.14-1.29 (8H, m), 1.81 (4H, s), 1.95-2.00 (2H, m), 2.37 (6H, s), 3.02-3.24 (6H, m), 4.18-4.22 (5H, m), 4.64-4.65 (1H, d), 5.64 (2H, s), 6.72 (2H, s), 6.79 (1H, s), 7.30-7.32 (4H, d), 7.66-7.68 (1H, d), and 7.82-7.84(4H, d) Mass: 405.3 [M+H] +
Chiral HPLC: Eliglustat (100%), Other isomers (Not Detected)
Example 5: Preparation of N-((lR,2R)-l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-hydroxy- 3-(pyrrolidin-l-yl)propan-2-yl)octanamide (IX) (Eliglustat base)
To a stirred mixture of N-((lR,2R)-l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-hydroxy-3- (pyrrolidin-l-yl)propan-2-yl)octanamide di-p-tolyl-D-tartrate (40 g) in dichloromethane (200 ml) and water (225 ml), a 20% aqueous solution of potassium carbonate (100 ml) was added at 25- 30° C and stirred for 20 min. The layers were separated and the organic layer was washed with water (200 ml). The organic layer distilled out under vacuum to provide residue. Cyclohexane (40 ml) was added to the obtained residue and stirred for 30 min. The cyclohexane was distilled out under vacuum and then the residue degassed under vacuum to remove traces of solvent. Cyclohexane (200 ml) was added to the obtained residue and stirred for 1 h at 45-55° C. The reaction mixture was cooled to 25-35° C and stirred for 1 h. The solid was filtered and washed with cyclohexane (20ml X 2). The solid was dried at 25-35° C for 2 h and then at 45-55° C for 4 h to give the title product (19.5 g).
Example 6: Preparation of amorphous eliglustat hemitartrate
To a stirred mixture of N-((lR,2R)-l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-hydroxy-3-
(pyrrolidin-l-yl)propan-2-yl)octanamide (100.0 g) and water (350 ml), a solution of L-(+) tartaric acid (18.5 g) in water (50 ml) was added at 25-35° C. The reaction mixture was stirred at 25-35° C for 30 min. and at 40-50° C for 30 min. After completion of the reaction, the reaction mixture was filtered and then distilled out under vacuum to provide residue. The obtained residue was stirred in cyclohexane (500 ml) at 25-35° C for 1 h. The solid was filtered and dried at 25-35°C under vacuum to give the title product.
Example 7: Preparation of amorphous eliglustat hemitartrate
To a stirred mixture of N-((lR,2R)-l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-hydroxy-3- (pyrrolidin-l-yl)propan-2-yl)octanamide di-p-tolyl-D-tartrate (100.0 g) in toluene (500 ml) and water (700 ml), a solution of sodium hydroxide (11.1 g) in water (50 ml) was added at 40-50° C and stirred for 30 min. The layers were separated, and the organic layer was washed with water (200 ml X 2). The organic layer was filtered through a Hyflo bed and washed with toluene. A solution of L-(+) tartaric acid (9.4 g) in water (200 ml) was added to the obtained toluene layer at 25-35°C and stirred for 30 min. The layers were separated, and the aqueous layer (containing product)was filtered to remove particulate matter and washed with water (50 ml). The aqueous layer was distilled out under vacuum below 60° C to provide residue. Water (75 ml) was added to the residue at 35-45°C and stirred to provide a clear solution. The obtained solution was dried in a vacuum tray dryer at 35-45°C for 2 h and then at 45-55° C for 12 h. The obtained product was further dried in a vacuum tray dryer at 45-55°C until the water content was not more than 1.0 %w/w to give the title product (49.89 g).
1H NMR (DMSO-d6)5: 0.84-0.87 (3H, t), 1.07-1.09 (2H, m), 1.10-1.36 (8H, m), 1.75 (4H, m), 1.98-2.03 (2H, m), 2.50-2.55 (1H, m), 2.75 (4H, m), 2.89-2.94 (1H, m), 3.94 (1H, s), 4.08-4.10 (1H, m), 4.18 (4H, s), 4.66-4.67 (1H, d), 6.72-6.73 (2H, d), 6.78 (1H, s) and 7.46-7.49 (1H, d).
Example 8: Preparation of amorphous eliglustat hemitartrate
To a stirred mixture of N-((lR,2R)-l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-hydroxy-3- (pyrrolidin-l-yl)propan-2-yl)octanamide di-p-tolyl-D-tartrate (25.0 g) in toluene (125 ml) and water (175 ml), aqueous ammonia solution (-20% w/v) was added at 25-35° C to adjust the pH between 9.5 to 11 and stirred for 30 min. The layers were separated and the organic layer was washed with dilute aqueous ammonia solution (-2% w/v) (50 ml) followed by water (50 ml X 3). The organic layer was filtered through a Hyflo bed and washed with toluene (25 ml). A solution of L-(+) tartaric acid (2.37 g) in water (50 ml) was added to the obtained toluene layer at 25-35° C and stirred for 30 min. The layers were separated, and the aqueous layer (containing product)was filtered to remove particulate matter and washed with water (7 ml). The aqueous layer was distilled out under vacuum below 60° C to provide residue. Water (18 ml) was added to the residue and stirred to provide a clear solution. The obtained solution was dried in a vacuum tray dryer at 35-45° C for 2 h and then at 40-50° C for 12 h. The obtained product was further dried in a vacuum tray dryer at 40-50° C until the water content not more than 1% w/w to give the title product (12.42 g).
Example 9: Preparation of stable amorphous form of eliglustat hemitartrate
A mixture of eliglustat hemitartrate (12.0 g) and toluene (120 ml) was heated to reflux at 108- 110° C for 3-5 h. The reaction mixture was then allowed to warm at room temperature, and the toluene was decanted from the reaction mixture to provide a gummy residue. Diisopropyl ether (40ml) was added to the residue and stirred for 30 min. at room temperature. The resulting suspension was filtered under vacuum and washed with diisopropyl ether (10ml). The solid was dried under vacuum at 50-55° C for 4-6 h to give the title compound. The resulting material was packed under nitrogen atmosphere. The obtained amorphous form of eliglustat hemitartrate was characterized by X-ray diffraction pattern as depicted in Fig. 1.
Residual solvent content (toluene): 0.01wt%. The obtained amorphous eliglustat hemitartrate was kept in an open air having about 36% humidity for 20 h to evaluate any change in the water content and thus its hygroscopicity. The change in the total weight of amorphous eliglustat hemitartrate found 0.02%, indicating a low degree of hygroscopicity.
Example 10: Preparation of stable amorphous form of eliglustat hemitartrate
A mixture of eliglustat hemitartrate (12.0 g) and toluene (120 ml) was heated to reflux at 108- 110° C for 3-5 h. The reaction mixture was then distilled out under vacuum to provide gummy residue. Cyclohexane (60 ml) was added to the residue and stirred for 30 min. at room temperature. The resulting suspension was filtered under vacuum and washed with cyclohexane (12 ml). The solid was dried under vacuum at 50-55° C for 4-6 h to give the title compound. The resulting material was packed under nitrogen atmosphere.
Residual solvent content (toluene): 0.01wt%.
When amorphous eliglustat hemitartrate was placed at a temperature of 25 +2° C at a relative humidity of 60 +5% for 1 month, no change was observed in the XRPD pattern, indicating that the amorphous eliglustat hemitartrate described herein is stable.

Claims

CLAIMS:
1. A process for preparation of eliglustat or its tartrate salt, comprising
(a) reacting racemic eliglustat of formula II)
Figure imgf000030_0001
with a chiral acid in the presence of a suitable solvent to provide a chiral acid salt; optionally purifying the chiral acid salt;
(b) reacting the chiral acid salt with a suitable base to provide eliglustat free base of formula
(ix)
Figure imgf000030_0002
(IX)
optionally purifying the eliglustat free base in a suitable solvent; and
(c) optionally reacting the eliglustat free base of formula (IX) with L-(+) -tartaric acid in the presence of a suitable solvent to provide eliglustat tartrate.
2. The process as claimed in claim 1, wherein the chiral acid is selected from the group consisting of: mandelic acid, malic acid, camphor sulfonic acid, di-p-toluoyl-D-tartaric acid, di- m-toluoyl-D-tartaric acid, and di-benzoyl-D-tartaric acid.
3. The process as claimed in claim 1, wherein the suitable solvent in (a) is selected from the group consisting of: methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, dichloromethane, chlorobenzene, chloroform, and mixtures thereof.
4. The process as claimed in claim 1, wherein the suitable base in (b) is selected from the group consisting of: sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.
5. The process as claimed in claim 1, wherein the suitable solvent in (c) is selected from the group consisting of: hydrocarbons, alcohols, ketones, water, and mixtures thereof.
6. The process as claimed in claim 1, wherein the suitable solvent in (c) is selected from the group consisting of: toluene, xylene, methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, water, and mixtures thereof.
7. A process for preparation of eliglustat or its tartrate salt, comprising :
(a) reacting racemic eliglustat of formula (VII)
Figure imgf000031_0001
(VII)
with di-p-toluoyl-D-tartaric acid in the presence of a suitable solvent to provide di-p- toluoyl-D-tartrate salt of formula III)
Figure imgf000031_0002
(Will)
optionally purifying the di-p-toluoyl-D-tartrate salt of formula (VIII);
(b) reacting the eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) with a suitable base to provide eliglustat free base of formula (IX)
Figure imgf000031_0003
optionally purifying the eliglustat of formula (IX) in a suitable solvent; and
(c) optionally reacting the eliglustat of formula (IX) with L-(+) -tartaric acid in the presence of a suitable solvent to provide eliglustat tartrate.
8. A process for preparation of racemic eliglustat of formula (VII) comprising:
(a) reacting 2,3-dihydrobenzo [l,4]dioxine of formula (II)
Figure imgf000031_0004
(Π) with chloroacetyl chloride to provide 2-chloro-l-(2,3-dihydrobenzo[b][l,4]dioxin-6- yl)ethan-l-one of formula (III) which is in situ reacted with an aminating agent and hydrochloric acid to provide a hydrochloride salt of 2-amino-l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl ethan-l-one of formula (IV)
Figure imgf000032_0001
(b) reacting the compound of formula (IV) with octanoic acid or one or more derivatives thereof in the presence of a suitable solvent to provide N-(2-(2,3- dihydrobenzo[b][l,4]dioxin-6- -2-oxoethyl)octanamide of formula (V)
Figure imgf000032_0002
(V)
(c) reacting the compound of formula (V) with paraformaldehyde and pyrrolidine to provide
N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l-yl)propan-2- yl)octanamide of formula I)
Figure imgf000032_0003
(VI)
optionally treating the compound of formula (VI) with oxalic acid in the presence of a suitable solvent to provide an oxalate salt of formula (VI); and
(d) reacting the compound of formula (VI) or its oxalate salt with a suitable reducing agent to provide racemic eliglustat of formula (VII)
Figure imgf000032_0004
(VII)
9. The process as claimed in claim 8, wherein the aminating agent is selected from the group consisting of: hexamine, ammonia, and mixtures thereof.
10. The process as claimed in claim 8, wherein the suitable solvent in (b) is selected from the group consisting of: halogenated hydrocarbons, hydrocarbons, ethers, and mixtures thereof.
11. The process as claimed in claim 8, wherein the suitable solvent in (b) is selected from the group consisting of: dichloromethane, chlorobenzene, chloroform, toluene, xylene, tetrahydrofuran, diethyl ether, and mixtures thereof.
12. The process as claimed in claim 8, wherein the suitable reducing agent in (d) is selected from the group consisting of: palladium, palladium-carbon, palladium hydroxide-carbon, platinum oxide, copper chromite, palladium acetate, platinum-carbon, palladium-alumina, Raney nickel, sodium bisulfite, sodium sulfite, sodium pyrosulfite, ammonium sulfite, ammonium sulfite monohydrate, ammonium bisulfite, tetra methyl ammonium borohydride, tetra ethyl ammonium borohydride, tetra-n-butyl ammonium borohydride, tetra-n-butyl ammonium cyanoborohydride, sodium cyanoborohydride, lithium cyanoborohydride, sodium borohydride, potassium borohydride, lithium aluminum hydride, diborane, and mixtures thereof.
13. The process as claimed in claim 8, wherein suitable reducing agent in step (d) is selected from the group consisting of: sodium borohydride, potassium borohydride, and mixtures thereof.
14. A process for preparation of eliglustat or its tartrate salt, comprising :
(a) reacting eliglustat di- -toluoyl-D-tartrate salt of formula (VIII)
Figure imgf000033_0001
(VIII)
with a suitable base to provide eli lustat free base of formula (IX)
Figure imgf000033_0002
(ιχ) ; and
(b) optionally reacting eliglustat of formula (IX) in situ with L-(+) -tartaric acid
presence of a suitable solvent to provide eliglustat tartrate.
A process for recycling racemic eliglustat of formula (VII) or its salt, comprising : (a) reacting mother liquor obtained after isolation of eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII)
Figure imgf000034_0001
(Vlll)
with an oxidizing agent followed by epimerization to provide a compound of formula (VI)
Figure imgf000034_0002
<VI) ; and
(b) reducing the compound of formula (VI) to provide a racemic eliglustat of formula (VII)
Figure imgf000034_0003
(VII)
16. A compound selected from:
Figure imgf000034_0004
(V)
Figure imgf000034_0005
(VI) Oxalate
Figure imgf000035_0001
(VIII)
and pharmaceutically acceptable solvates and hydrates thereof. 17. A stable amorphous form of eliglustat hemitartrate of formula (I)
Figure imgf000035_0002
18. The stable amorphous form of eliglustat hemitartrate of claim 17, which remains stable towards conversion to crystalline form at a temperature of 25° C at relative humidity of 60 +5% for a time period of at least 1 month.
19. The stable amorphous form of eliglustat hemitartrate of claim 17, which remains stable towards conversion to crystalline form at a temperature of 5° C for a time period of at least 1 month.
20. The stable amorphous form of eliglustat hemitartrate of claim 17, which is non-hygroscopic.
21. The stable amorphous form of eliglustat hemitartrate of claim 17, wherein the change in total weight of amorphous eliglustat hemitartrate is less than 0.5 weight percent upon exposure to an atmosphere of about 36% humidity for 20 hours. 22. The stable amorphous form of eliglustat hemitartrate as claimed in claim 17, characterized by an X-ray diffraction pattern substantially as depicted in Fig. 1.
23. The stable amorphous form of eliglustat hemitartrate as claimed in claim 17, characterized by an X-ray diffraction pattern substantially as depicted in Fig. 2.
24. The stable amorphous form of eliglustat hemitartrate as claimed in claim 17, which is substantially free of residual solvent.
25. The stable amorphous form of eliglustat hemitartrate as claimed in claim 24, which has residual solvent content of 0.01 weight % or less.
26. The stable amorphous form of eliglustat hemitartrate as claimed in claim 17, which substantially free from eliglustat N-oxide im urity of formula (X)
Figure imgf000036_0001
(X)
A process for preparation of stable amorphous eliglustat hemitartrate comprising:
(a) suspending eliglustat hemitartrate in a suitable solvent and removing the solvent to obtain a residue;
(b) adding a suitable solvent to the residue; and
(c) obtaining the amorphous form of eliglustat hemitartrate.
28. The process of claim 27, wherein the suitable solvent in (a) is selected from the group consisting of: hydrocarbons, alcohols, ketones, esters, nitriles, ethers, polar aprotic solvents, and mixtures thereof.
29. The process of claim 27, wherein the suitable solvent in (a) is selected from the group consisting of: toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, and mixtures thereof.
30. The process of claim 27, wherein the suitable solvent in (b) is selected from the group consisting of: ethers, hydrocarbons, and mixtures thereof.
31. The process of claim 27, wherein the suitable solvent in (b) is selected from the group consisting of: diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran,
1,4-dioxane, 2-methoxyethanol, toluene, xylene, hexane, cyclohexane, heptane, and mixtures thereof.
32. The process of claim 27, wherein the stable amorphous eliglustat hemitartrate shows no change in XRPD pattern when it is placed at a temperature of 25 ±2° C at relative humidity of 60 +5% for 1 month and at a temperature of 5 ±2° C for 1 month.
33. The process of claim 27, wherein the stable amorphous eliglustat hemitartrate is obtained by removal of solvent.
34. The process of claim 33, wherein the solvent may be removed by filtration or decantation..
35. A pharmaceutical composition comprising the stable amorphous form of eliglustat hemitartrate according to claim 17 and one or more pharmaceutically acceptable carriers, excipients or diluents.
36. Use of a stable amorphous form of eliglustat hemitartrate according to claim 17 for treatment of Gaucher disease.
PCT/EP2018/060185 2017-04-21 2018-04-20 Process for preparation of eliglustat hemitartrate and intermediates thereof WO2018193090A2 (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110759885A (en) * 2018-07-27 2020-02-07 中国医学科学院药物研究所 Method for preparing photoactivated Igutate
CN110878079A (en) * 2018-12-31 2020-03-13 北京启慧生物医药有限公司 Preparation method of high-purity eliagliptat
US10888547B2 (en) 2009-11-27 2021-01-12 Genzyme Corporation Amorphous and a crystalline form of genz 112638 hemitartrate as inhibitor of glucosylceramide synthase
EP3941917A4 (en) * 2019-03-22 2022-12-21 Piramal Pharma Limited An improved process for the preparation of eliglustat and its intermediate
CN118284600A (en) * 2021-11-12 2024-07-02 曙方(上海)医药科技有限公司 Pharmaceutically acceptable salts of irinotecan and crystalline forms thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6916802B2 (en) 2002-04-29 2005-07-12 Genzyme Corporation Amino ceramide-like compounds and therapeutic methods of use
US7196205B2 (en) 2001-07-16 2007-03-27 The Regents Of The University Of Michigan Synthesis of UDP-glucose: N-acylsphingosine glucosyltransferase inhibitors
US20130137743A1 (en) 2009-11-27 2013-05-30 Genzyme Corporation Amorphous and a crystalline form of genz 112638 hemitartrate as inhibitor of glucosylceramide synthase
WO2016001885A2 (en) 2014-07-03 2016-01-07 Dr. Reddy’S Laboratories Limited Amorphous form of eliglustat hemitartarate
CN105646442A (en) 2015-10-27 2016-06-08 北京凯莱天成医药科技有限公司 Preparation method of eliglustat

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2313001T3 (en) * 2003-05-13 2009-03-01 F. Hoffmann-La Roche Ag 2-IMIDAZO-BENZOTIAZOLES AS LEGANDS OF ADENOSINE RECEPTORS.
FR2864628B1 (en) * 2003-12-30 2006-02-17 Commissariat Energie Atomique RADIATION DETECTION SYSTEM WITH DOUBLE RESET PULSE COUNTER

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7196205B2 (en) 2001-07-16 2007-03-27 The Regents Of The University Of Michigan Synthesis of UDP-glucose: N-acylsphingosine glucosyltransferase inhibitors
US6916802B2 (en) 2002-04-29 2005-07-12 Genzyme Corporation Amino ceramide-like compounds and therapeutic methods of use
US20130137743A1 (en) 2009-11-27 2013-05-30 Genzyme Corporation Amorphous and a crystalline form of genz 112638 hemitartrate as inhibitor of glucosylceramide synthase
WO2016001885A2 (en) 2014-07-03 2016-01-07 Dr. Reddy’S Laboratories Limited Amorphous form of eliglustat hemitartarate
CN105646442A (en) 2015-10-27 2016-06-08 北京凯莱天成医药科技有限公司 Preparation method of eliglustat

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10888547B2 (en) 2009-11-27 2021-01-12 Genzyme Corporation Amorphous and a crystalline form of genz 112638 hemitartrate as inhibitor of glucosylceramide synthase
US11458119B2 (en) 2009-11-27 2022-10-04 Genzyme Corporation Amorphous and a crystalline form of genz 112638 hemitartrate as inhibitor of glucosylceramide synthase
CN110759885A (en) * 2018-07-27 2020-02-07 中国医学科学院药物研究所 Method for preparing photoactivated Igutate
CN110759885B (en) * 2018-07-27 2021-10-22 中国医学科学院药物研究所 Method for preparing photoactive igloot
CN110878079A (en) * 2018-12-31 2020-03-13 北京启慧生物医药有限公司 Preparation method of high-purity eliagliptat
EP3941917A4 (en) * 2019-03-22 2022-12-21 Piramal Pharma Limited An improved process for the preparation of eliglustat and its intermediate
CN118284600A (en) * 2021-11-12 2024-07-02 曙方(上海)医药科技有限公司 Pharmaceutically acceptable salts of irinotecan and crystalline forms thereof

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